Telmisartan, 4′-[2-n-propyl-4-methyl-6-(1-methylbenzimid-azol-2-yl)benzimidazol-1-ylmethyl]biphenyl-2-carboxylic acid, having the structure of formula I
is a non-peptide angiotensin II receptor (type AT1) antagonist. The United States Food and Drug Administration (FDA) approved it for the treatment of hypertension. It may be used alone or in combination with other hypertensive agents, such as hydrochlorothiazide. Boehringer Ingelheim markets telmisartan under the trade name Micardis® (telmisartan), available as 40 and 80 mg tablets for oral administration. Two patents are listed in the FDA's electronic Orange Book for telmisartan, U.S. Pat. No. 6,358,986 (“the '986 patent”) and U.S. Pat. No. 5,591,762 (“the '762 patent”).
The '986 patent discloses that telmisartan and the physiologically acceptable salts thereof can also be used to treat cardiac insufficiency, ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), diabetic neuropathy, glaucoma, gastrointestinal diseases, bladder diseases, and to prevent progression of cardiac insufficiency after myocardial infarct.
In addition to the above therapeutic applications of telmisartan, the '762 patent discloses other therapeutic applications, including treating diabetic nephropathy, pulmonary diseases, e.g., lung oedema and chronic bronchitis. It also discloses using telmisartan to prevent arterial restenosis after angioplasty, thickening of blood vessel walls after vascular operations, and diabetic angiopathy. The '762 patent further discloses using telmisartan to alleviate central nervous system disorders, such as depression, Alzheimer's disease, Parkinson Syndrome, bulimia, and disorders of cognitive function in view of the effects of angiotensin on the release of acetylchloline and dopamine in the brain.
The European Application No. EP 0502314 and its corresponding U.S. patent, the '762 patent disclose preparing telmisartan by alkylation of 1,7′-dimethyl-2′-propyl-1H, 3′H-[2,5′] bibenzoimidazolyl (referred to as BIM) with a 4′-[(bromomethyl)[1,1′-biphenyl]-2-carboxylic acid 1,1-dimethylethyl ester (referred to as a BMBP alkyl ester) followed by hydrolysis.
Chinese patent application, CN 1344712A, filed July 2001 discloses a process to prepare telmisartan by reacting 1,7′-dimethyl-2′-propyl-1H, 3′H-[2,5′]bibenzoimidazolyl with 4′-bromomethyl-biphenyl-2-carboxylic acid methyl or ethyl ester to form a telmisartan methyl or ethyl ester intermediate, which is converted to telmisartan by acid or base hydrolysis.
BIM may be prepared by mixing 2-propyl-4-methyl-1H-benzimidazole-6-carboxylic acid with N-methyl-o-phenylene-diamine dihydrochloride as disclosed in J. Med. Chem. (1993), 36(25), 4040-51, International Patent Application WO 0063158, and US Application No. 2003/0139608 and are hereby incorporated by reference for their disclosure of processes for preparing BIM. US Application No. 2003/0139608 discloses a process, which can be used on an industrial scale for preparing and purifying BIM, in which the crude product is subjected to charcoal treatment.
The BMBP alkylester, wherein the alkyl group is a C1-4 branched or straight chain may be prepared as disclosed in EP Patent No. 253,310, Meyers et al., Tetrahedron 1985 vol. 41, 837-860, European Patent No 324,377, and Japanese Patent No. 06298684. Each of these references is hereby incorporated by reference for their disclosure of processes for preparing a BMBP alkylester.
The solvents previously used to prepare telmisartan, such as dimethylformamide and dimethylsulfoxide, have a high boiling point of greater than about 150° C. These solvents are difficult to remove from the reaction using various evaporation techniques known in the art. These reaction conditions are less environmentally friendly, less efficient, and harsher on the product, and therefore result in a lower yield of the telmisartan alkylester intermediate product. Other previously used solvents to prepare telmisartan are miscible with water and therefore cause difficulties in extracting the organic telmisartan alkylester intermediate products from the reaction. Other solvents are toxic or unsafe for other reasons. Also, processes previously disclosed use 1.5 equivalents of BIM for each equivalent of a BMBP alkyl ester, which is in excess of what is theoretically required. The expense of the reagents in the preparation and isolation of BIM results in a more expensive overall synthesis of telmisartan than should theoretically be required.
Thus, there is a need for processes for the preparation of telmisartan alkylester and telmisartan that are environmentally friendly, easy to practice, produce high yields of telmisartan, less costly and that can be adapted to industrial scale.